Temporal lobe epilepsy (TLE) is the most common refractory form of partial epilepsy in adults. There is growing evidence from gene discovery, association and family studies for a genetic contribution to human TLE. However, most TLE remains unexplained by genes discovered to date, and genetic as well as clinical heterogeneity complicate investigations. The fundamental goal of this project is to discover genes influencing susceptibility to TLE, using a multidisciplinary, translational approach that combines a mouse model, computational genomics methods and a human genetic association study. We aim to use the differential response of inbred mouse strains to toxin-induced limbic seizures as a phenotype for quantitative trait locus (QTL) mapping of the seizure susceptibility trait. We will use computational genomics methods to select and prioritize biologically meaningful candidate genes that map to the regions identified. These strategies will also be used to generate new candidates. During the Award period we will begin a candidate gene-based association study of human temporal lobe epilepsy patients. Homologues of mouse candidates, genes reported in association with TLE in prior studies and genes identified through computational strategies can be tested in this design. The combination of human and animal research strategies in a multidisciplinary study design, particularly when further strengthened by computational genomics and database mining techniques, provides a powerful approach to provide novel and important contributions to the understanding of temporal lobe epilepsy genetic susceptibility. The proposed 5-year Development Award is intended to provide the applicant with additional training and experience in three areas: The use of mouse epilepsy models, computational genomics and the conduct of a large-scale candidate gene allelic association study. Experts in each of these fields will be collaborating on the project and contributing to this training. The candidate is the recipient of a K23 Award that has supported her development as an independent genetic epidemiologist and clinical scientist. The environment at Columbia University is ideally suited for this multidisciplinary project, with clinical epileptologists, molecular biologists, statisticians, computational biologists, geneticists, genetic epidemiologists and experts in animal models of epilepsy in one institution, able to forge powerful collaborations.